|Year : 2016 | Volume
| Issue : 3 | Page : 98-131
Synthetic approaches and potential bioactivity of different functionalized quinazoline and quinazolinone scaffolds
Mohsen M Kamel1, Wafaa A Zaghary2, Reem I Al-Wabli3, Manal M Anwar1
1 Department of Therapeutical Chemistry, National Research Centre, Pharmaceutical and Drug Industries Research Division, Dokki, Egypt
2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Cairo, Egypt
3 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
|Date of Submission||15-Mar-2016|
|Date of Acceptance||30-May-2016|
|Date of Web Publication||5-Jan-2017|
Manal M Anwar
Department of Therapeutical Chemistry, National Research Centre, Pharmaceutical and Drug Industries Research Division, El-Bohowth Street, PO Box 12622, Dokki, 0123456, Cairo
Source of Support: None, Conflict of Interest: None
Drug discovery and optimization constitutes one of the most important targets in medicinal chemistry. Because of their wide bioactivity spectra, nitrogen-containing heterocycles have received significant attention in many bio(organic) studies. The current review is a simple summary of different environmentally benign synthetic procedures that afford a variety of quinazoline and quinazolinone scaffolds with promising biological potential. The molecular modeling of various classes has also been discussed to elucidate the molecular reasons that led to the observed inhibition profile of different protein kinases, including which amino acids in their active sites would be involved in the anticipated bonding interactions. Furthermore, this article aims to investigate which classes deserve further development to get more specific and more potent quinazoline and quinazolinone candidates in various biological targets.
Keywords: biological activities, molecular docking, protein kinase inhibitors, quinazoline, quinazolinone, synthesis
|How to cite this article:|
Kamel MM, Zaghary WA, Al-Wabli RI, Anwar MM. Synthetic approaches and potential bioactivity of different functionalized quinazoline and quinazolinone scaffolds. Egypt Pharmaceut J 2016;15:98-131
|How to cite this URL:|
Kamel MM, Zaghary WA, Al-Wabli RI, Anwar MM. Synthetic approaches and potential bioactivity of different functionalized quinazoline and quinazolinone scaffolds. Egypt Pharmaceut J [serial online] 2016 [cited 2021 Jul 29];15:98-131. Available from: http://www.epj.eg.net/text.asp?2016/15/3/98/197580
| Introduction|| |
Quinazoline 1 is 1,3-diazanaphthalene. This nucleus is also called 5,6-benzopyrimidine or benzo[a]pyrimidine or phenmiazine . Its 4-oxo derivative is named 4(3H)-quinazolinone 2 ([Figure 1]) . Depending on the wide spectra of their different pharmacological activities, both nuclei have attracted considerable attention from many scientists and chemists worldwide. They exhibit antimalarial , antimicrobial , anti-inflammatory , anticonvulsant , antihypertensive , antidiabetic , and antitumor activities ,,. At the same time, various quinazoline derivatives are considered, such as inhibitors of various forms of cellular phosphorylation , in addition to their essential activities in the central nervous system (CNS), such as ligands for benzodiazepine and γ-aminobutyric acid receptors . Also, many quinazoline derivatives act as DNA-binding agents or as effective adrenergic blockers .
|Figure 1: Chemical structures of quinazoline 1 and 4(3H)-quinazolinone 2.|
Click here to view
Many quinazolinone derivatives also constitute the building blocks for about 150 natural alkaloids isolated from various classes of the plant kingdom, from microorganisms, and from animals ([Figure 2]). Earlier studies conducted in the 1950 s and 1960 s led to the discovery of febrifugine, a quinazolinone alkaloid, which possesses antimalarial potential, from the Chinese plant aseru (Dichroa febrifuga Lour) .
|Figure 2: Structures of alkaloids incorporating quinazolinone frameworks.|
Click here to view
| Chemistry of quinazolines|| |
Gabriel  was the first scientist to prepare quinazoline nucleus in the laboratory in 1903. Widdege  was the first scientist to propose the name quinazoline (German: chinazolin) for this nucleus on the basis of its appearance as an isomer with the quinoxaline ring .
The synthesis of various compounds containing quinazoline as the main nucleus is largely based on the substitution patterns on the 1,3-diazine moiety of the system.
The facile preparation of quinazolin-4(3H)-one (4), which involves heating the logical starting material anthranilic acid (3) with excess formamide in an open container at 120°C, was known as Niementowski reaction ([Figure 3]) . In addition, Ahmed et al. used formyl anthranilamide (5) for the preparation of 4 by means of intramolecular condensation reaction ([Figure 3]).
|Figure 3: Preparation of 4(3H)-quinazolinone using anthranilic acid or formyl anthranilamide.|
Click here to view
The 7-chloro-substituted derivative (7)  has been prepared through condensation of 4-chloroanthranilic acid amide (6) with triethyl orthoformate ([Figure 4]).
2-Substituted-4(3H)-quinazolinones and quinazolines
The general method for producing the cinnamamide derivative 10 involves the treatment of 2-aminobenzonitrile (8) with 3-phenyl cinnamoyl chloride (9). Under alkaline conditions, intramolecular cyclization was carried out to afford 2-styryl-4(3H)-quinazolinone (11)  ([Figure 5]). This procedure was tolerated to a wide range of different substituted benzene rings, and in most cases the intermediate N-(2-cyanophenyl)cinnamamide (10) could be isolated.
Refluxing of anthranilamide (12) with aryl, alkyl, or heteroaryl aldehydes or ketones (13) in 2, 2, 2-trifluoroethanol in the absence of catalysts led to the formation of 2-substituted-2,3-dihydro-4(1H)-quinazolinones (14) in excellent yields. The characteristic physiochemical properties of fluorous solvents, such as low nucleophilicity, high polarity, and high ability of hydrogen bond donation, has led to their utilization in organic reactions ([Figure 6]) .
|Figure 6: Preparation of 2-substituted-2,3-dihydro-4(1H)-quinazolinones. TFE, 2,2,2-trifluoroethanol.|
Click here to view
Microwave (MW) conditions were used by Rad-Moghadam and Mohseni  to synthesize 2-substituted-4(3H)-quinazolinones (16). This strategy involved the reaction of anthranilic acid (3), ammonium acetate, and orthoesters (15) to yield the desired products ([Figure 7]).
Complete conversion of anthranilic acid (3) to 2-substituted-4(3H)-quinazolinones was gained in efficient yields (75–84%) under MW conditions over 10 min at a temperature of 200°C at 200 W. Heating anthranilic acid (3), acetic anhydride, and formamide in a sealed tube at 200°C (200 W) for 10 min leads to rapid decomposition of formamide during the interaction of anthranilic acid and anhydride. The formed ammonia (in situ) reacts with the benzoxazine derivative (17). An efficient yield of 3-methylquinazolin-4-one (18) was achieved after purification ([Figure 8]) .
|Figure 8: Preparation of 3-methylquinazolin-4-one under microwave (MW) conditions.|
Click here to view
Abdel-Jalil et al.  revealed that the intermediate Schiff's bases (19) were synthesized in good yields within 3 h at 70 °C through treatment of anthranilamide (12) with suitable aldehydes in ethyl alcohol. The conversion of Schiff's bases to the corresponding 2-substituted quinazolinones (16) was carried out within 2 h in refluxing ethanol containing three equivalents of copper chloride. However, these quinazolinones (16) could be also obtained in 88% yield through a one-step reaction procedure by refluxing ethanolic solution of anthranilamide (12), the appropriate aldehyde, and copper chloride for 2–3 h ([Figure 9]).
Erba et al.  introduced a three-component reaction to obtain 2-alkylquinazolines (22). First, a suitable aldehyde was allowed to react with morpholine to form the intermediate (20). In the second step, compound 20 was treated with an aryl azide to obtain the 1, 2, 3-triazoline derivatives (21) in good yields. Further, the triazolines (21) were exposed to an ethanolic solution saturated with ammonia in a sealed vessel at 150°C to afford the desired quinazoline products (22). Alternatively, the same compounds (22) could be obtained when the triazolines (21) were treated with ammonium acetate in boiling toluene within half an hour. The intramolecular cyclization of the triazolines afforded the 2-alkylquinazoline derivatives (22) in 92–95% yields ([Figure 10]).
Kotsuki et al.  developed condensation of cyano-activated and nitro-activated o-fluoro-benzaldehydes (23) with amidine (24) to afford different substituted quinazoline derivatives (25) in promising yields. Cyclization of the imine with the aldehydic functional group occurred. Nucleophilic substitution of the fluorine atom was carried out leading to intramolecular cyclization to afford the quinazoline derivatives (25). The reaction was performed under reflux in acetonitrile containing potassium carbonate in the presence of powdered molecular sieves. Chromatographic purification was carried out for the crude products ([Figure 11]).
|Figure 11: Preparation of different substituted quinazoline derivatives.|
Click here to view
The amino-quinazolin-4(3H)-one (28) was derived by Hess et al. . It was synthesized by means of the reaction of the corresponding methyl anthranilate (26) with an excess amount of guanidine (27) in ethyl alcohol containing sodium ethoxide. The yield of this reaction was moderate ([Figure 12]).
Clark and Wagner  have reported the use of isatoic acid anhydride (29) for the preparation of 3-substituted-4(3H)-quinazolinone derivatives (30) by heating with primary amines and triethyl orthoformate ([Figure 13]).
Majo and Perumal  developed the 3-substituted-4(3H)quinazolinones (34 and 35) in which the Vilsmeier reagent (chloromethyleneiminium salt) (32) reacted with 5-substituted-2-amino benzoic acid derivatives (31) to give the corresponding acid chlorides (33), which reacted through two possible routes: A and B ([Figure 14]).
Because of the reported high biological potential of 4-arylaminoquinazolines as anticancer agents, there has been renewed interest in their syntheses . Amidines (36) were readily formed by the interaction of 2-aminobenzonitrile (8) with different substituted anilines and anhydrous aluminum chloride. It was observed that the highest yield of the amidine intermediates 36 was achieved by the use of excess amounts of suitable aniline and aluminum chloride. Limited production of the intermediates (36) was obtained from the pattern of aromatic substitution on the aniline ring. 2-Aminobenzonitrile (8) did not react with 3,4-dichloroaniline or nitroanilines possibly because the nucleophilicity of the amino functionality is minimized in each case. Good yields (70–92%) of the 4-arylaminoquinazoline derivatives (37) were achieved when the 2-amino-N-arylbenzamides (36) were heated with 85% formic acid ([Figure 15]) .
An efficacious method for the preparation of 4-anilinoquinazolines (40) was reported by Tsou et al. . Condensation of 5-nitroanthranilonitrile (38) with dimethylformamide-dimethyl acetal yielded compound 39. When compound 39 was heated with 3-bromoaniline in acetic acid it afforded the target quinazoline derivative (40) in an outstanding yield. This method is beneficial as the synthesis of the quinazoline ring system and its conjugation with the 4-anilino moiety take place in the same step ([Figure 16]).
The treatment of (E)-N′-(2-cyano-3-fluorophenyl)-N,N-dimethylformimidamide (41) with 2-chlorobenzylamine (42) to obtain the quinazoline compound 43 using MW irradiation was reported by Yoon et al.  ([Figure 17]).
|Figure 17: Preparation of N-(2-chlorobenzyl)-1-(5-fluoroquinazolin-4-yl)methanamine derivatives. MW, microwave.|
Click here to view
Ager et al.  obtained 2,3-disubstituted-4(3H)-quinazolinone derivatives (45) through the treatment of N-acylanthranilic acid (44) with the appropriate aryl amines in the presence of phosphorous oxychloride ([Figure 18]).
|Figure 18: Preparation of 2,3-disubstituted-4(3H)-quinazolinone derivatives.|
Click here to view
Furthermore, a group of researchers  reported that the 3-substituted-2-metyl quinazolinones (47) were prepared by the reaction of methyl-2-acetamido benzoate (46) with the desired amine in the presence of trimethyl aluminum in 1,2-dichloroethane ([Figure 19]).
Benzoxazinone derivatives are the most common intermediates in the formation of 2,3-disubstituted quinazolinone derivatives. Welch et al.  stated that refluxing of anthranilic acid (3) with acetic anhydride in acetic acid yielded 2-methyl-4H-benzo[d] [1,3]oxazin-4-one (17), which was heated with amines in acetic acid or ethanol to yield the corresponding quinazolinones (48) ([Figure 20]).
Dandia et al. disclosed that the 4-benzoxazinone derivative (50) was synthesized in situ by the cyclodehydration of 2-phenylacetylamino benzoic acid (49) with acetic anhydride using inorganic solid supports. Also, the condensation of the 4-benzoxazinone derivative (50) with various para/meta/ortho-substituted anilines has been studied to obtain the desired derivatives (51 and 52) ([Figure 21]).
|Figure 21: Preparation of 3-substituted-2-benzylquinazolin-4(3H)-one derivatives.|
Click here to view
Moreover, a rapid one-step MW reaction by cyclocondensation of anthranilic acid (3), phenyl acetyl chloride (53), and different substituted aniline derivatives for the synthesis of quinazoline derivatives 54 was documented by Dandia et al.. The reaction yield was 87–92% ([Figure 22]) .
|Figure 22: Preparation of 3-substituted-2-benzylquinazolin-4(3H)-one derivatives.|
Click here to view
Lee et al.  developed a facile method for the formation of 3-substituted-2-cyano-4(3H)-quinazolinone compounds (57) in moderate to good yields by the treatment of primary alkylamines with the intermediate derivative (56). The latter compound was synthesized by the treatment of methyl anthranilate (26) with 4,5-dichloro-1, 2, 3-dithiazolium chloride (Appel's salt) (55) in pyridine. Its yield was 50%. The cyano group of quinazolinone products (57) could be replaced by different nucleophiles to furnish the corresponding 2-substituted quinazolinone derivatives in high yields. This leads to the synthesis of new quinazoline systems rapidly and efficiently ([Figure 23]).
|Figure 23: Preparation of 3-substituted-2-cyano-4(3H)-quinazolinone derivatives. THF, tetrahydrofuran.|
Click here to view
2,4-Disubstituted-4(3H)-quinazolinones and quinazoline
The synthesis of 4-aminoquinazolines (58) using MW irradiation was documented by Seijas et al. . This reaction was performed by the treatment of the cyanoaromatic derivatives with anthranilonitrile (8) in a MW oven. 2-(Thiophen-2-yl)quinazolin-4-amine was gained at a high yield by heating anthranilonitrile, 2-thienylnitrile, and potassium tert-butoxide in a test tube for 60 s. A remarkable decrease in reaction time, the absence of solvents, and the use of a base in a catalytic amount are attractive features of this method ([Figure 24]).
|Figure 24: Preparation of 4-aminoquinazoline derivatives. MW, microwave; t-BUOK, potassium tert-butoxide.|
Click here to view
Mizuno et al.  reported the preparation of 2,4-dihydroxyquinazoline derivatives using various 2-aminobenzonitrile compounds 8 and carbon dioxide containing 1,8-diazabicyclo [5, 4, 0]undec-7-ene under mild conditions. The reaction was carried out using a suitable base to synthesize the carbamate salt (59). In the subsequent step the oxygen of carbamate moiety attacked the nitrile group, leading to nucleophilic cyclization. Then, rearrangement took place to produce the intermediate (60), which was protonated to give the target 2,4-dihydroxyquinazolines (61) ([Figure 25]).
|Figure 25: Preparation of 2,4-dihydroxyquinazoline derivatives. DBU, 1,8-diazabicyclo[5,4,0]undec-7-ene.|
Click here to view
The thermolysis of 5-methoxy-(3H)-1,4-benzodiazepines to furnish 4-methoxyquinazoline derivatives was studied by Kaname et al. . Ring contraction was the proposed mechanism. The 4-methoxyquinazoline derivatives (63) were the only obtained products in moderate yields (41–46%) upon heating the 5-methoxy-(3H)-1,4-benzodiazepines (62) in refluxing diphenyl ether at 160–170°C for 6 h ([Figure 26]).
Zielinski et al.  developed a procedure to synthesize dimethylquinazoline-2,4-diamine derivatives by treating chloroamidines with dialkylcyanamides. Reaction of various phenyl isocyanate derivatives (64) with N,N-diethylamine led to the formation of the substituted urea derivatives (65), which were subsequently chlorinated with phosphorus pentachloride to produce the corresponding compounds (66). As an example, 2-(N,N-diethylamino)-4-(N,N-dimethylamino)quinazoline (68) was synthesized in 79% yield by cyclization of compound 67, which was obtained by the treatment of chloroamidine (66) with N,N-dimethylcyanamide ([Figure 27]).
The reaction of various Grignard reagents with 2-aminobenzonitrile (8) resulting in the formation of intermediates (69) was demonstrated by Bergman et al.. The formed derivatives (69) were very important for obtaining many types of quinazoline derivatives. Upon their cyclization with acid chlorides, anhydrides, and formates they formed the corresponding quinazoline derivatives in moderate to good yields. This general method for the preparation of various 2,4-disubstituted quinazoline derivatives is highly flexible and useful ([Figure 28]).
|Figure 28: Preparation of various 2,4-disubstituted quinazoline derivatives.|
Click here to view
| Pharmacological applications|| |
Aurora proteins inhibitors
Aurora proteins constitute a small class of serine/threonine kinases that are generated during the period of mitosis. They play important functions in chromosomal segregation and cytokinesis. There are three types of aurora kinases formed in human beings: aurora A, B, and C. These protein kinases have been recently considered attractive drug targets because of their importance in mitosis and their irregular overexpression in cancer cells . Inhibition of both aurora A and aurora B causes the formation of different cellular phenotypes. Synthesis of a set of 5-acetanilide-3-aminopyrazole(3-pyrazole)-substituted quinazoline derivatives that showed high selectivity for aurora B over aurora A resulted in the synthesis of AZD1152 ([Figure 29]). AZD1152 has exhibited significant anticancer activity in different preclinical models and was recently used in phase I clinical experiments . Taking into consideration the structural characteristics of AZD1152, a novel class of 1-acetanilide-4-aminopyrazole-substituted quinazoline compounds (compounds 70) was formed by Foote et al. .
|Figure 29: Structures of quinazoline derivatives as aurora protein inhibitors.|
Click here to view
In summary, it has been observed that the 4-pyrazole derivatives exhibited significant inhibition against aurora B kinase, whereas less activity was observed against aurora A. Potent cellular activities were achieved by the presence of fluoro groups favorably at C2 and C3 of the phenyl ring. The conjugation of different basic side chains with the quinazoline ring system at C7 also delivered high activity. The displacement of the methoxy group with a proton at quinazoline-C6 enhanced the selectivity for aurora B over aurora A. The cellular potency for the 4-pyrazole derivatives is significant and even higher than that of the corresponding 3-pyrazole analogs. Many 4-pyrazole derivatives exhibited cellular EC50 less than 10 nmol/l and some, such as compounds 70, showed cellular EC50 less than 1 nmol/l ([Figure 29]). The optimized compound 71 exhibited potency at doses less than that in other reported series in preclinical in-vivo models ([Figure 29]).
Topoisomerase (I and II) inhibitors
Benzimidazole–quinazoline hybrids, substituted with various secondary amines, demonstrate the effects of electron-donating and electron-accepting nitrogen groups within the groups ,. Lipophilicity of polar compounds, an important property for the activity of different drugs, increases because of the attachment of alkyl or allyl functionalities to the benzimidazole ring and aryl moieties to the quinazoline ring ([Figure 30]).
Novel regioisomeric hybrids (3-allyl-2-methyl-3H-benzimidazol-5-yl)–(2-substituted-quinazolin-4-yl)-amine derivatives (72–75) and (1-allyl-2-methyl-1H-benzimidazol-5-yl)–(2-substituted-quinazolin-4-yl)-amine derivatives (76–77) were derived by Sharma et al. and evaluated as novel compounds for their anticancer activity. Preliminary in-vitro antitumor screening proved that the derivatives 72 and 73 had potent inhibitory effect (>60%) for the growth of most of the tested tumor cell lines, whereas all the compounds exhibited selective activity toward the renal cancer cell line A498. Also, the anticancer evaluation confirmed that (3-allyl-2-methyl-3H-benzimidazol-5-yl)–(2-amino-quinazolin-4-yl)-amine derivatives (72, 73, and 75) are more effective anticancer compounds than their regioisomeric analogs (1-allyl-2-methyl-1H-benzimidazol-5-yl)–(2-aminoquinazolin-4-yl)-amine derivatives 76 and 77 ([Figure 31]). Molecular docking studies of compound 73 indicated that the formation of hydrogen bonds with the active sites of ribonucleotide reductase, topoisomerase I, and topoisomerase II also enhanced its potency. These benzimidazole and quinazoline hybrids could be further used as anticancer compounds of significant potency. Further derivatization and optimization studies of the anticancer profiles of these compounds are currently ongoing.
|Figure 31: Structures of hybrids of benzimidazole and quinazoline analogs.|
Click here to view
Dual Src/Abelson murine leukemia viral oncogene homolog 1 (Abl) kinase inhibitors
The design and preparation of various new 4-benzothiazole amino quinazoline analogs were carried out by Cai et al.  ([Figure 32]). The synthesis of these novel hybrids depends on the structure–activity relationship (SAR) analysis of dasatinib, which was used as the leading compound, and also on the basic drug design principles of ring addition and combination.
In-vitro cytotoxic activity evaluation by MTT-based assay was carried out for all target compounds. The activity was investigated against six human cancer cell lines (HCT-116, DLD1, K562, U937, A549, and NCI-H661). The obtained data showed that most of the tested derivatives exhibited a remarkable growth inhibition against the six cell lines compared with the parental dasatinib. In addition, the target compounds were tested as Src and Abl kinase inhibitors. The enzyme inhibitory assay showed that the derivatives bearing 2-methyl piperidine moiety attached to the quinazoline ring are the most potential dual Src/Abl kinase inhibitors. Thus they are potential lead ligands to be prepared and optimized as alternatives for the current dasatinib therapy or for patients who show imatinib resistance, potentially by simultaneously blocking multiple receptor tyrosine kinase (RTK) signaling pathways ([Figure 32]).
Epidermal growth factor receptor and vascular endothelial growth factor receptor 2 inhibitors
Novel 2-chloro-4-anilino-quinazolines were designed and examined as inhibiting agents for both epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR-2) protein kinases . It has been documented that EGFR and VEGFR-2 are validated targets in cancer therapy, and combined inhibition might be synergistic for both antitumor activity and resistance prevention. The results of the enzyme inhibitory test proved that 2-chloro-4-anilino-quinazoline derivatives produced potential activity against both EGFR and VEGFR-2. Compound 79e was nearly seven times more active against VEGFR-2 and nearly 11 times more active against EGFR in comparison with the prototype 78 that was previously synthesized by Abouzid and Shouman . SAR and molecular docking studies investigated the pharmacophoric moieties for both EGFR and VEGFR-2 protein kinases and investigated the worth of the presence of a hydrogen bond donor at the aniline-C4 for binding with the conserved glutamate and aspartate amino acids in the binding sites of both EGFR and VEGFR-2, which promotes a significant increase in potency ([Figure 33]).
Also, new 6,7-disubstituted-4-(arylamino)quinazoline derivatives were synthesized by Zhang et al. . These compounds were developed to function as irreversible inhibiting agents for the EGFR protein kinase. Fortunately, they revealed significant activity. Compared with afatinib, some of them revealed significant enhanced potency against H1975 cells (EGFR-T790 M). Moreover, the optimized compounds 80 and 81 also showed acceptable pharmacokinetic properties and oral bioavailability. Depending on the developed safety and activity against EGFR-T790 M resistance, the derivatives 80 and 81 could be used for further development and optimization in future research ([Figure 34]).
|Figure 34: Structures of 6,7-disubstituted-4-(arylamino) quinazoline derivatives.|
Click here to view
Erythropoietin-producing hepatocellular receptor tyrosine kinase A inhibitors
The erythropoietin-producing hepatocellular (Eph) RTKs play very important roles in various physiological and pathological conditions, including embryogenesis, patterning, neuronal targeting, vascular development, and cancer progression. There is overexpression of Eph RTKs and their cell-presented ligands, ephrins, in a large number of cancer types such as breast, lung, gastrointestinal cancers, and neuroblastomas. At present, there are two main classes of Eph RTKs: EphA (EphA1–10) and EphB (EphB1–6) . EphA2 has particularly been correlated to breast, prostate, lung, ovarian, and cervical cancer as well as to malignant melanoma. Further, the degree of malignancy and poor prognosis depend on the level of EphA2 expression in the tumor cells. Novel 4-substituted quinazoline derivatives bearing the 7-(morpholin-2-ylmethoxy) group (compounds 82) were designed and prepared by Lim et al. . The new derivatives showed significant inhibition toward EphA2. The most potent compound was 82e ([Figure 35]).
|Figure 35: Structures of 4-substituted quinazoline derivatives bearing 7-(morpholin-2-ylmethoxy) group.|
Click here to view
Poly(ADP-ribose)polymerase-1 enzyme inhibitors
It was demonstrated that poly(ADP-ribose)polymerase-1 (PARP-1) plays a pivotal role in the repair of single-strand breaks of DNA through the base excision repair pathway. Therefore, the inhibition of PARP-1 enzyme can synergize the cytotoxic effects of the DNA-damaging agents [e.g. temozolomide (TMZ), cyclophosphamide, and camptothecin], which cause lesions normally repaired by the base excision repair pathway . Novel 1-benzyl-quinazoline-2,4(1H,3H)-dione derivatives were designed and prepared as human PARP-1-inhibiting agents. Depending on the SAR studies, it was found that the quinazoline-2,4(1H,3H)-diones (83) produce potent inhibitory activity against the PARP-1 enzyme of IC50 values at nanomolar levels. Compound 83c produced a potent dual-inhibition effect against PARP-1 and PARP-2 and it could selectively damage the breast cancer cells MX-1 and MDA-MB-468 with mutated BRCA1/2 and PTEN, respectively, compared with homologous recombination proficient cell types such as the breast cancer cell line MDA-MB. Moreover, compound 83c exhibited the strongest potentiation effect of potentiation factor (PF50) on TMZ in MX-1 cells (PF50 = 3.77) ([Figure 36]).
|Figure 36: Structures of 1-benzyl-quinazoline-2,4(1H,3H)-dione derivatives.|
Click here to view
Nitrogen mustards are the earliest bifunctional alkylating agents. They interrupt DNA biosynthesis, leading to DNA disruption and damage. The biggest disadvantage of these drugs is their high genotoxicity, which produces many side effects on the patients . Many nitrogen mustards have been synthesized in clinical applications. Chlorambucil, melphalan, and cyclophosphamide are the most important drugs belonging to this class. Hoping to obtain novel potential antiproliferative derivatives, a new class of quinazoline-nitrogen mustards (compounds 84, 85, and 86) were designed and synthesized by Li et al. . In this work, a nitrogen mustard group was directly introduced to the quinazoline ring depending on its efficiency as an ideal carrier for nitrogen mustards.
Most of the new quinazoline-nitrogen mustard derivatives revealed selective cytotoxicity toward specific types of cancer cells, and the conjugation of the quinazoline ring generally reduced the virulent side effects of the nitrogen mustard. Various studies have demonstrated that compound 85b shows cell cycle delay and arrests the cell cycle progression predominantly at the S and G2/M boundary, and produces cell apoptosis, while its host toxicity is small. Thus, this work revealed some methods for synthesis and optimization of new quinazoline-nitrogen mustards of high tumor affinity taking quinazoline ring as a nitrogen mustard transporter ([Figure 37]).
Antimitotics and tubulin polymerization inhibiting activity
A novel class of pyrrolo [3,4-h]quinazolines has been successfully prepared by fusion of the pyrimidine ring with the isoindole moiety ([Figure 38]) . Some of the new compounds have shown interesting cytotoxicity in many tumor cell lines and were active even in a multidrug-resistant cell line. The most cytotoxic derivatives, 87a–d and 88e, induced cell death mainly by apoptosis, as demonstrated by the onset of the apoptotic peak in cell cycle analysis and by the classical annexin-V/PI test. Moreover, the involvement of mitochondria and, in a later stage, of lysosomes was demonstrated. It was observed that most cytotoxic quinazoline derivatives act as antimitotics and inhibit tubulin polymerization in vitro. These derivatives also presented some antiangiogenic effects that could be useful for disrupting the tumor vascular network, thus inducing extensive cell death at its core.
A new set of 6-chloro-2-p-tolylquinazolinone compounds (89 and 90) and 9-chloro-5-p-tolyltetrazolo [1,5-c]quinazoline (91) was prepared in order to examine them as in-vitro anticancer agents ([Figure 39]) . The tested candidates were examined against 60 cancer cell lines at 10 μmol/l concentration. The obtained data showed that compounds 89 and 90 had significant wide-spectrum antitumor potency. The derivative 91 selectively inhibited the growth of non-small-cell lung cancer using 5-fluorouracil as a reference drug. Also, it was demonstrated that compound 90 had ∼1.5 fold more potency (mean GI50 = 15.8 μmol/l) in comparison with 5-fluorouracil (mean GI50 = 22.6 μmol/l).
|Figure 39: Structures of 6-chloro-2-p-tolylquinazolinone (89, 90) and 9-chloro-5-p-tolyltetrazolo[1,5-c]quinazoline (91) derivatives.|
Click here to view
Mitochondrial translocator protein inhibiting activity
Glioblastoma multiforme (GBM) is the most common and malignant primary human brain tumor with very poor prognosis. Patients diagnosed with GBM usually undergo surgical intervention by Food and Drug Administration for the treatment of late-stage metastatic medullary thyroid cancer, as well as resection, radiation, and chemotherapy using the DNA alkylating agent TMZ, but the mean life expectancy is less than 14 resistance induction because of the activation of DNA repair proteins rendering the drug ineffective . Recent reports indicated that the mitochondrial translocator protein is selectively overexpressed in the brains of GBM patients. In this regard, compounds inducing the mitochondrial permeability transition pore (mPTP) opening through translocator protein targeting were suggested as chemotherapeutic agents for glioma and glioblastoma cells. Elkamhawy et al.  reported on novel quinazoline-urea compounds ([Figure 40]). In this study, the mPTP opening was aimed to be inhibited. Most of the bulky derivatives of R2 of the urea side chain exhibited an opposite effect on the mitochondrial membrane potential, which could be a promising approach for GBM therapy. The eight compounds 92 showed excellent selectivity indices for GBM cells compared with a normal astrocyte cell line. Compound 92e manifested potent tumoricidal effects on TMZ-resistant GBM cells even at submicromolar concentrations accompanied by a safe toxicity profile. Taken as a whole, this report presents compound 92e as a potent, selective, and safe GBM cytotoxic agent, giving new promise for action against TMZ-resistant GBM.
Transcription factor protein complex (nuclear factor κB) inhibiting activity
Nuclear factor κB (NF-κB) is a transcription factor protein complex. It is present in almost all animal cell types and plays a pivotal role in some tumors and inflammatory responses. It increases the rate of proliferation and inhibits apoptosis, in addition to creating more blood flow to ensure the survival of cancer. Thus, blocking the NF-κB pathway is one of the most important approaches in the cancer therapeutic field. A new class of quinazoline scaffold pharmacophores (93 and 94) of expected high binding affinity with the p50 subunit of NF-κB was designed and synthesized ([Figure 41]) . Biological studies showed that the compounds carrying phenyl substituents at the quinazoline-C2 position appeared to be potent inhibitors of NF-κB function. These candidates also reduced the proliferation rate of many cancer cell lines. The compound 93c exhibited a mean GI50 of 2.88 μmol/l against the NCI-60 cell lines and produced a remarkable apoptosis in the EKVX cell line at a dose of 1 μmol/l.
Inducing apoptosis activity
Novel compounds of m-(4-morpholinoquinazolin-2-yl)benzamides were designed, prepared, and characterized by Wang et al.  ([Figure 42]). The new derivatives were examined as anticancer agents against two types of human cancer cells (HCT-116 and MCF-7). Most of the candidates exhibited potent antiproliferative activity, especially compound 96, which represented a significant in-vitro potency in the Hoechst staining assay. Furthermore, the cell cycle and apoptosis assay showed that the analog 96 might arrest HCT-116 cells in G2/M and G0/G1 phase and lead to apoptosis. Also, compounds 95 and 96 exhibited selective inhibition of the PI3Kα enzyme, as revealed by the enzyme assay results. Also, western bolt assay proved that analog 96 could block the PI3K/Akt/mTOR pathway. These results directly revealed m-(4-morpholinoquinazolin-2-yl)benzamide derivatives as new antitumor candidates. The SAR of the title compounds reveals that the benzamide moiety is important for the maintenance of the antiproliferative activity of the title compounds. In addition, a trifluoromethoxy moiety at m-position of the amide group and methoxy at six and seven positions of the quinazoline ring are also favorable substituents.
|Figure 42: Structures of m-(4-morpholinoquinazolin-2-yl)benzamide derivatives.|
Click here to view
Molecular hybridization led to the design and synthesis of new isatin–quinazoline hybrids ([Figure 43]) . The new hybrids were examined as in-vitro anticancer agents against the liver HepG2, breast MCF-7, and colon HT-29 cancer cell lines. Significant selective inhibition was gained against the HepG2 cancer cell line. The derivatives 97a, 97b, and 97c produced the strongest activity (IC50 = 1.0–2.4 μmol/l). Further, they led to apoptosis in HepG2 cells, as seen by increased proapoptotic protein Bax expression and decreased expression of the antiapoptotic protein Bcl-2, as well as enhanced caspase-3 levels.
Marketed anticancer drugs carrying quinazoline core
The drugs gefitinib (Iressa), erlotinib (Tarceva), and lapatinib (Tykerb) ([Figure 44]), which selectively inhibit the EGFR protein kinase, were approved by the Food and Drug Administration in 2003, 2004, and 2007, respectively. They are active in locally advanced or metastatic cancer chemotherapy ,,,. Vandetanib, targeting EGFR and VEGFR-2, was approved in April 2011.
|Figure 44: Chemical structures of different anticancer drugs carrying quinazoline pharmacophores.|
Click here to view
New basic 5,6-dihydrobenzo[h]quinazoline derivatives 98a–h carrying various amino groups at positions 2 and 4 were designed and synthesized in order to obtain novel antiplatelet/analgesic and anti-inflammatory agents with a safe gastrointestinal profile ([Figure 45]) .
The new derivatives (98a–h) exhibited variable antiplatelet activity on the in-vitro platelet aggregation test. The derivatives 98a and 98e emerged as having the strongest activity by inhibition of all the aggregating stimuli. The in-vivo examination found that the conjugation of different amino groups at position 4 was important for producing the analgesic potency of compounds 98a–h – in particular, compound 98 h. This derivative exhibited 51% pain inhibition at a dose that did not lead to any sedation as the treated mice exhibited the same degree of locomotor activity as those treated with the vehicle only, in the same experiment. Data showed that 98a and 98 h inhibited both cyclooxygenase (COX) 1 (maximal inhibition = 50.5 and 28.7%, respectively) and COX2 (maximal inhibition = 38.6 and 50.7%, respectively) at a dose of 1 mmol/l. These data confirm the hypothesis that both 98a and 98 h have promising antiplatelet activity with no relation to COX inhibition, acting through other modes of action. Computational study on compounds 98a and 98 h was also performed. Docking simulation studies of both compounds showed that compound 98a directed the dihydrobenzo[h]quinazoline portion toward Tyr355, Leu523, and Leu531 and can form one H-bond with the key residue Tyr385 through the aniline moiety nitrogen atom, whereas the anilino group of compound 98 h is directed toward Leu523, Leu531, and Tyr355 without forming any H-bonds with the Ser530 or Tyr385 key residues.
Tumor necrosis factor (TNF)-α is one of the most common inflammatory mediators in different inflammatory diseases, such as rheumatic arthritis. The compound 2-chloro-N-(4-(2-morpholinoethoxy)phenyl)quinazolin-4-amine (99) was discovered by Pu et al. . It inhibits TNF-α production (IC50 = 8.86 μmol/l in RAW264.7 cells), leading to promising inflammatory activity. In-vivo study revealed that compound 99 was a potent antiarthritic candidate as it enhanced the arthritic score, decreased the infiltration of inflammatory cells, and protected the joints from destruction ([Figure 46]).
Furthermore, novel 4-amino quinazoline derivatives were synthesized. They were tested as anti-inflammatory agents in lipopolysaccharide (LPS)-induced macrophages  ([Figure 46]). The four most active derivatives 100a, 100b, 100c, and 100d showed inhibition of TNF-α and interleukin-6 release depending upon the used concentration. The results revealed that derivatives 100b and 100d, especially 100d, alleviated lung histopathological changes, inflammatory cell infiltration, and cytokine mRNA expression initiated by LPSs. In view of these results, this study proved that 100b and 100d could alleviate acute lung injury by in-vivo and in-vitro inhibition of the inflammatory response. Thus, it was indicated that various quinazolines could act as potential relieving agents in acute lung injury and serve as basic scaffolds in drug development and research.
A novel class of 2,3-dihydro-2-(substituted-phenyl)pyrazolo [5,1-b]quinazolin-9(1H)-ones was reported by Hussein et al. . The new derivatives were examined for their anti-inflammatory activity using diclofenac sodium as a reference standard. The tested compound 101 showed remarkable potency when compared with the reference drug ([Figure 47]).
|Figure 47: Structures of different quinazolone derivatives with anti-inflammatory activity.|
Click here to view
At the same time, Eweas et al.  designed and prepared new 2-pyridyl(3H)-quinazolin-4-one derivatives for anti-inflammatory evaluation. The whole evaluated compounds showed promising activity comparable to that of the standard drug indomethacin. Among them, compounds 102 and 103 revealed the most potent anti-inflammatory activity.
New quinazolin-4(3H)-one derivatives were prepared by Saravanan et al.  for anti-inflammatory evaluation. The derivatives that were substituted with halogen atoms, particularly those carrying trifluoromethyl groups, revealed potent anti-inflammatory activity. Among all tested compounds, trifluoromethyl analog 104 exhibited more potent activity compared with diclofenac ([Figure 47]).
Farag et al.  reported the synthesis of novel 3-(4-chlorophenyl or 4-fluorophenyl)-6-iodo-4-oxo-3,4-dihydroquinazoline derivatives carrying Schiff bases and various heterocyclic motifs such as oxazolone, imidazolidine, pyrazolidine, pyridine, and pyrimidine ([Figure 47]). The anti-inflammatory evaluation in chronic models showed that 3-(4-fluorophenyl)-2-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-ylimino)-methyl]-6-iodo-3H-quinazolin-4-one (105), which has –N = CH–pyrazoline moiety at C2 position and fluorophenyl at C3 position, produced the strongest anti-inflammatory activity. Other derivatives such as 106 and 107 incorporating –N = CH-substituted pyrazoline moieties at C2 positions also showed potent anti-inflammatory activity but slightly less than that of compound 105.
Al-Salahi et al.  prepared a novel set of 2-methylsulfanyl- [1, 2, 4]triazolo [1,5-a]quinazoline derivatives ([Figure 48]). The new analogs were tested as anti-inflammatory agents. The tested samples showed varying degrees of anti-inflammatory activity. Some compounds showed potential potent anti-inflammatory activity with respect to that of dexamethasone and the control, which varied from 75 to 86% inhibition, comparable to that of LPS-induced cells. Some others possessed moderate activity, with inhibition ranging from 50 to 70%. Overall, these results indicated that compounds 108–112 are promising multipotent anti-inflammatory agents.
|Figure 48: Structures of 2-methylsulfanyl-[1,2,4]triazolo[1,5-a]quinazoline derivatives.|
Click here to view
Zayed and Hassan  prepared novel analogs of 6,8-diiodo-2-methyl-3-substituted-quinazolin-4(3H)-ones carrying sulfonamide moieties ([Figure 49]). The newly synthesized derivatives were examined as anti-inflammatory candidates using the carrageenan-induced hind-paw edema test. Ibuprofen was used as a reference standard. Among the screened compounds, 113 and 114 with aliphatic side chains showed higher activity than those bearing aromatic moieties. Compound 114 was found to be the most active one with a relative potency of 74% of the ibuprofen potency.
|Figure 49: Structures of 6,8-diiodo-2-methyl-3-substituted-quinazolin-4(3H)-ones.|
Click here to view
The quinazoline ring system is considered the ‘master key’ in anticonvulsant therapy. It constitutes the basic scaffold of many common anticonvulsant drugs ,. Examples of the potent anticonvulsant drugs containing quinazoline core are mentioned in [Figure 50].
|Figure 50: Some of the potent anticonvulsant drugs bearing the 4(3H)-quinazolinone ring.|
Click here to view
In medicinal chemistry, the 4(3H)-quinazolinone scaffold is considered one of the most important heterocycles for synthesis of various anticonvulsant agents. Many studies have reported that the attachment of a methyl group at position 2 and a substituted aromatic ring at position 3 of the 4(3H)-quinazolinone ring is essential for CNS depression and anticonvulsant activities. Novel 2, 3, 8-trisubstituted-4(3H)-quinazoline derivatives were prepared and assessed as antiepileptic agents, being compared with the reference drugs methaqualone and sodium valproate . Compounds 2- [3,4-dihydro-2-methyl-3-(2-methylphenyl)-4-oxoquinazolin-8-yloxy]acetic acid hydrazide (115), ethyl-2-[2-(2-methyl)-3-(2-methylphenyl)-4(3H)-quinazolin-8-yloxy) acetyl]hydrazincarboxylate (116), and methyl-2-[2-(2-methyl-3-(2-methylphenyl)-4(3H)-quinazolin-8-yloxy)acetyl]hydrazinecarbodithioate (117) ([Figure 51]) produced the strongest activity in this class with relatively low neurotoxicity. The resultant data showed that the most potent analogs could serve as basic templates for further optimization and development to obtain more potent anticonvulsant candidates.
Also, a new set of 2-aryl-6,7-methylenedioxy-3H-quinazolin-4-ones was prepared and examined for their antiepileptic activity. They are considered to be prototypes of the 2,3-benzodiazepine core structure, thus providing a rationale for compounds 118, 119, and 120 to demonstrate significant anticonvulsant and neuroprotective actions ([Figure 52]) .
|Figure 52: Structures of novel 2-aryl-6,7-methylenedioxy-3H-quinazolin-4-ones.|
Click here to view
Also, Colotta et al. prepared new 3-hydroxyquinazoline-2,4-diones carrying a trifluoromethyl group at quinazoline-C7 position and different functionalities at C6 position. Glycine (Gly)/N-methyl-D-aspartate receptor (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA), and kainic acid (KA) receptor binding data showed that the 7-trifluoromethyl moiety improved the affinity and selectivity toward AMPA and KA receptors compared with the 7-chlorine atom. In the new class, 6-(1, 2, 4-triazol-4-yl) derivative 121 ([Figure 53]) exhibited the most affinity and selectivity toward the AMPA receptor, displaying efficient anticonvulsant activity with decreasing neuronal damage .
|Figure 53: Structure of the 6-(1,2,4-triazol-4-yl)-quinazoline derivative.|
Click here to view
According to the molecular docking results of compound 121, the quinazoline ring exhibited hydrogen bonding with iGluRs: Arg96, Thr91, and Pro89 at the AMPA receptor ([Figure 55]) and with Arg131, Thr126, and Pro124 at the Gly/NMDA receptor. The NH group of the compound acts as a proton donor toward the backbone C = O of Pro89, whereas the 2-carbonyl group accepts a hydrogen bond from the backbone –NH– of Thr91 at the AMPA receptor site. Moreover, both 2-carbonyl and 3-hydroxy groups interact with the side chain of Arg96. The triazole nucleus accepts a hydrogen bond from the Thr174 side chain.
A novel class of 1,9-disubstituted-8-chloro-pyrazolo [1,5-c]quinazoline-2-carboxylates was prepared by Varano et al.. The binding affinities of the new derivatives toward AMPA, Gly/NMDA, and KA receptors were tested. The obtained data revealed that the attachment of 1,2-dicarboxylic acid groups and suitable substituted benzene moieties to the basic pyrazole-quinazolinone core (compounds 122) ([Figure 54]) was essential to obtain new selective candidates of AMPA receptor antagonistic action.
|Figure 54: Structures of different pyrazolo[1,5-c]quinazolinone derivatives.|
Click here to view
At the same time, a class of new 3-[5-substitutedphenyl-1, 3, 4-thiadiazole-2-yl]-2-styryl quinazoline-4(3H)-ones (compounds 123) ([Figure 55]) was synthesized by Jatav et al.. The anticonvulsant activity evaluation exhibited that the derivatives bearing phenyl, p-chlorophenyl, and m-chlorophenyl substituents on the thiadiazole ring had promising antiepileptic potency in the MES screen. When tested for neurotoxicity, the derivative bearing a phenyl residue on the thiadiazole moiety displayed promising potency devoid of neurotoxicity.
|Figure 55: Structures of 1,3,4-thiadiazole-quinazoline-4(3H)-one derivatives.|
Click here to view
The antiepileptic and inhibitory activity against the monoamine oxidase enzyme of different methaqualone analogs ([Figure 56]) was tested by Misra et al. . It was observed that quinazolines possessing hydramide moiety had selective antiepileptic activity. The attachment of the 2-hydroxy-3,5-dichlorophenyl group at the Ar-moiety enhances the antiepileptic potency. At the same time, in the case of hydrazide analogs, the attachment of a chlorine atom at position 2 of the phenyl ring and a styryl residue at position 2 of the quinazolone ring also enhances the antiepileptic activity.
It has been noted that 6-chloro-3-(4-benzhydrazide)-2-(2′-chlorostyryl)-4-quinazolones (compounds 124) produced the strongest antiepileptic potency and produced 60% protection against Pentylenetetrazole (PTZ)-induced seizures in mice.
3-Hydroxy-quinazoline-2,4-diones (compounds 125) have been designed and synthesized by Catarzi et al. ([Figure 57]). The affinity toward the AMPA receptor was assessed by the new quinazolinone derivatives. The data obtained showed that conjugation of a N3-nitrogen-containing heterocycle at position 8 of the basic backbone plays a very important role in inducing potency and selectivity toward the AMPA receptor. Also, the introduction of potent electron-withdrawing groups, such as chlorine atom, trifluoromethyl, or nitro substituents at position 7 of the quinazolinone heterocycle, enhanced the activity and selectivity toward the same target .
The novel derivative 5-phenyl- [1, 2, 4]triazolo [4,3-c]quinazolin-3-amine (126) was synthesized by Zheng et al. ([Figure 58]). This derivative exhibited promising antiepileptic activity (ED50 = 27.4 mg/kg). Compound 126 exhibited clonic seizure inhibition by 30%, and absolute protection against the tonic seizures. It has been demonstrated that the antiepileptic potency of compound 126 was mediated by the γ-aminobutyric acid) system .
|Figure 58: Structure of the [1,2,4]triazolo[4,3-c]quinazoline derivative.|
Click here to view
El-Azab and El-Tahir  have synthesized new 7-substituted-4(3H)-quinazolinone compounds . The new derivatives were evaluated as anticancer and anticonvulsant agents. Compounds 127, 128a,b, and 129a,b showed remarkable antiepileptic activity with lower neurotoxicity compared with the standard drugs methaqualone and valproate ([Figure 59]). The most potent agents were selected for further examinations at various concentrations for quantification of their antiepileptic potency. The compounds exhibited ED50 values of 0.74, 0.31, 0.35, 0.70, and 0.40 mmol/kg, respectively. Methaqualone and valproate showed ED50 values of 1.40 and 1.5 mmol/kg, respectively. Interestingly, ED50 values of the tested agents appeared to be lower than those of the reference drugs at the same molar concentrations. The data revealed that these derivatives might be valuable scaffolds for further design and improvement in order to obtain more potent agents .
Kadi et al. produced a new class of 2-mercapto-3-(4-chlorophenyl)-4-oxo-6-iodoquinazolines ([Figure 60]). The antiepileptic potency of the new derivatives was evaluated using the PTZ seizure threshold test. Compounds 130–133 showed significant anticonvulsant activity with complete disappearance of seizures during the course of the assay. According to the obtained data, these compounds showed potent CNS depressant effects, accompanied by sedation and hypnosis .
|Figure 60: Structures of 2-mercapto-3-(4-chlorophenyl)-4-oxo-6-iodoquinazolines.|
Click here to view
New derivatives of the quinazolinedione nucleus conjugated with sulfonamide moieties were prepared by Orain et al.. The newly synthesized compounds appeared as competitive AMPA receptor antagonists with better characteristics, particularly compound 134 ([Figure 61]).
The central skeleton of 134 formed a favorable π–π stacking with Tyr450 and hydrogen bonds with the residues Pro478, Thr480, and Arg485. Additional hydrogen bonds were also formed by the derivative 134 with Thr686 and Glu402 (NH amide), which might be responsible for higher affinity .
Quinazoline-2,4-diones attached to sulfonamide groups have been prepared as a new set of effective competitive AMPA receptor antagonists of strong receptor affinity and significant oral in-vivo activity. Compound 135 ([Figure 62]) showed nanomolar receptor affinity .
|Figure 62: Structure of the quinazoline-2,4-dione-sulfonamide derivative.|
Click here to view
Koller et al. constructed the human receptor hGluA2 and successfully cocrystallized it with the antagonist 135. An X-ray structure investigated the binding mode of the two chemo types. Compound 135 was directed such that a favorable p-stacking with Tyr450 occurred and then formed the hydrogen bond. The sulfonamide nitrogen reacts with H3Np–Arg485, revealing that this nitrogen was negatively charged, which led to a strong Coulomb interaction. The ring –HN group exhibited significant hydrogen bonding interaction with the carbonyl group of Pro478. The imidazole moiety formed a hydrogen bond with the side chain hydroxyl group of Thr686, and the adjacent nitro substituent made water-mediated contact with Tyr405 and Thr707.
Patents for quinazolines as antiepileptics were recently granted at World Intellectual Property Organization (WIPO), United States Patent and Trademark Office (USPTO), and European Patent Applications and Specifications related to quinazolines. These patents proved that quinazolines are very useful in seizure disorders. Floersheim et al. claimed that quinazolines are effective pharmaceuticals in the treatment of epilepsy, especially in partial seizures (simple, complex, and partial evolving to secondarily generalized seizures) and generalized seizures [absence (typical and atypical), myoclonic, clonic, tonic, tonic–clonic, and atonic]. Further, the compounds of the general chemical structures 136 and 137 ([Figure 63]) were combined with other drugs to be more active in various conditions such as epilepsy. They could be combined with other anticonvulsants like barbiturates, benzodiazepines, carboxamides, hydantoins, succinimides, valproic acid, and other AMPA antagonists.
|Figure 63: Chemical structures of different quinazoline derivatives. R1 = alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, araalkynyl, heteroaralkyl, cyanoalkyl, azidoalkyl, alkoxyalkyl; R5 and R6 = hydrogen, halogen, haloalkyl, heterocyclic, heteroaryl, nitro, cyano, amino, thiol, carboxy, carbonylamido, thioalkoxy; R6 and R7 taken together to form a five or six membered carboxylic or heterocyclic rings; R8 = optionally substituted lower alkyl. X = O or S; Y = aryl or heteroaryl; n = z = 0 or 1.|
Click here to view
Floersheim et al. documented that quinazolines were valuable inhibitors of voltage-gated sodium channels and calcium channels. The invention also produced suitable quinazoline pharmaceuticals to treat different neurodegenerative diseases including seizure disorders. Also, they decreased the severity of trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, neurodegenerative disorders, and pychiatric disorders such as anxiety, depression, and myotonia ([Figure 64]).
|Figure 64: Chemical structures of quinazolines as inhibitors of ion channels. R1 and R2 are each independently an optionally substituted group selected from hydrogen C1–6 aliphatic. CY is a 5–7-membered monocyclic aryl ring or an 8–10-membered bicyclic aryl ring having 0–3 heteroatoms alkyl. R3 comprises alkylidend side chains.|
Click here to view
Treatment of Alzheimer's disease
The overproduction of β-amyloid (Aβ) peptide and its extracellular deposition is the most important factor associated with the etiology of Alzheimer's disease . Elkamhawy et al.  had synthesized a novel class of quinazoline-urea derivatives. Their blocking potency against Aβ peptide was assessed. Seven compounds, 139a–g ([Figure 65]), displayed higher potency compared with the standard cyclosporin A. MTT assay showed that the new candidates had excellent cellular viability. The quinazoline-urea compound 139 g, as the most active agent, produced activity that was two-fold higher than that of cyclosporin A, thus giving new direction for the design and synthesis of novel Aβ peptide blockers.
Xanthine oxidase inhibitory activity
Xanthine oxidase (XO) is a well-characterized druggable target in the treatment of diseases due to increased uric acid levels, such as hyperuricemia and gout, because of its significant role in catalytic oxidative hydroxylation of hypoxanthine and xanthine to produce uric acid. Further, XO is also associated with various diseases such as inflammation, metabolic disorders, cellular aging, reperfusion damage, atherosclerosis, hypertension, and carcinogenesis as it generates superoxide anions, H2O2, and highly reactive species (reactive oxygen species) during the catalytic process . Therefore, the selective inhibition of XO leads to therapeutical relief from gout, cancer, inflammation, and oxidative damage . Kumar et al.  designed and synthesized pyrazolo [1,5-c]quinazoline derivatives (compounds 140a–e) ([Figure 66]) to be tested as in-vitro XO inhibitors. The compounds 140d, 140e, and 140c significantly inhibited XO. The most potent XO inhibitor and free radical scavenger was compound 140d, when compared with allopurinol. The molecular docking of 140d into the XO active site highlighted its mode of binding and important interactions such as hydrogen bonding and π–π stacking with amino acid residues like Ser876, Thr1010, Phen914, Phe1009, and Phe649.
Toll-like receptors (TLRs) are critical components of the innate immune system that regulate immune recognition in part through NF-κB activation. A human cell-based high-throughput screen exhibited substituted 4-aminoquinazolines to be small-molecular-weight activators of NF-κB. Synthetic modifications of the quinazoline scaffold at the two and four positions led to the formation of the hit compound 141, which activated the interferon signaling pathway resulting in type I interferon production . The attachment of different moieties such as bromine, chlorine, and methyl at the orthoposition of the phenyl ring enhanced the immunological potency ([Figure 67]). Computational studies showed that the 4-aminoquinazoline compounds 142 bound primarily to human MD-2 in the TLR4/MD-2 complex. These molecules, which preferentially stimulate the human immune cells, may be valuable adjuvants or immunotherapeutic agents .
|Figure 67: Structures of novel substituted 4-aminoquinazoline derivatives.|
Click here to view
Clinical transplantation is a routine procedure, and its success is based on the matching of the major histocompatibility complex, on immune suppressive drugs, and on technical skills. Most transplants need immunosuppressants, which might be toxic, leading to cancer and infection. Induction of specific tolerance, which would inhibit the response to the graft without compromising host defense, is now characterized as the ‘holy grail’ of immunology. Sagiv-Barfi et al.  synthesized a new class of quinazoline derivatives that were examined as inhibitors of T-cell proliferation. N-p-tolyl-2-(3, 4, 5-trimethoxyphenyl)quinazolin-4-amine (143) ([Figure 68]) appeared to be the most potent analog inhibiting the growth of T cells with IC50 in the submicromolar range.
5-Hydroxy tryptamine2A receptor antagonistic activity
The 5-hydroxy tryptamine (5-HT)2A receptor is a G-protein-coupled receptor that generally mediates excitatory neurotransmission. One of the most fundamental biological functions of the 5-HT2A receptor is the regulation of dopamine release in three dopaminergic pathways. 5-HT2A is involved in a wide array of etiological processes including schizophrenia, depression, anxiety, migraine, hallucinations, insomnia, and addiction . Nevertheless, 5-HT2A antagonists have joined with D2 dopamine antagonists as the most frequently used atypical antipsychotic agents. A new class of compounds carrying the quinazoline nucleus was prepared and assessed as new effective 5-HT2A receptor ligands . Compound 144a ([Figure 69]) was particularly attractive as 5-HT2A and was discovered by pharmacophore-based virtual screening against the 5-HT2A receptor, followed by biological assays. Compound 144e is composed of a quinazoline core, an arm (piperazinyl-ethanol) and a tail (dimethoxy-aniline). Molecular modeling studies used this structural model to design and form a novel set of N-(substituted phenyl)-2-(piperazin-1-yl)quinazolin-4-amine derivatives (compound 144b–e). Compound 144e showed relatively high binding affinity to the 5-HT2A receptor (Ki = 14.04 nmol/l), as well as antagonist activity (IC50 = 1.66 μmol/l). This is the first time that quinazoline analogs have been discovered to be highly effective and selective ligands for the 5-HT2A receptor . Investigations of more potent and selective quinazoline derivatives are required for their practical and therapeutic applications in the future.
New 4-(substituted-phenyl)tetrazolo [1,5-a]quinazolin-5(4H)-ones ([Figure 70]) were designed and prepared to be tested as antidepressant agents . The biological assays revealed that derivatives 145a, 145b, and 145c at a dose of 50 mg/kg significantly decreased the immobility time of mice in the forced swimming test. The most potent derivative was 4-(p-tolyl)tetrazolo [1,5-a]quinazolin-5(4H)-one (145c), which reduced the immobility time by 82.69% at 50 mg/kg. This result was approximately equivalent to the antidepressant effect of fluoxetine. The underlying mechanisms of these compounds might be due to the regulation of the brain monoamine neurotransmitter homeostasis, based on the detected increased levels of noradrenaline and 5-HT and the reduced content of monoamine oxidase enzyme in mouse brain tissues.
|Figure 70: Structures of tetrazolo[1,5-a]quinazolin-5(4H)-one derivatives.|
Click here to view
Antidiabetes mellitus type 2
GPR119 is a G-protein-coupled receptor predominantly expressed in pancreatic β cells and intestinal enteroendocrine cells. GPR119 agonists enhance insulin secretion in vitro and reduce the elevated blood glucose level in vivo. In addition, they enhance the secretion of incretin (GLP-1 and GIP). Accordingly, GPR119 agonists were recently considered as important targets for the treatment of type 2 diabetes and obesity by controlling glucose homeostasis . New derivatives of 2,4-disubstituted quinazolines incorporated with heterocyclic alcohols and azabicyclic amine groups ([Figure 71]) have been synthesized and tested as GPR119 agonists. It has been shown that the derivatives carrying (2-fluoro-4-methylsulfonyl)phenylamino and azabicyclic amine groups with N-Boc (146a–c) have promising EC50 values. The obtained results suggested that the steric bulkiness of the attached groups enhanced the bioactivity, while the configuration (endo vs. exo) did not produce a remarkable effect. Better bioactivity was obtained by the electronic effects of the conjugated groups at position 2 of the benzene ring as well as the N-Boc group of azabicyclic amines. Further SAR studies to obtain more effective GPR119 agonists carrying different heterocyclic scaffolds are under progress .
|Figure 71: Structures of novel 2,4-disubstituted quinazoline derivatives.|
Click here to view
Melanin-concentrating hormone is a 19-amino-acid cyclic neuropeptide expressed predominantly in the lateral hypothalamus and zona incerta. The pivotal roles of melanin-concentrating hormone and the melanin-concentrating hormone receptor 1 (MCHR1) in the body weight and feeding regulation ensure the hypothesis that MCHR1 antagonists constitute new targets for the treatment of obesity . The quinazoline compounds 147, 148, and 149 ([Figure 72]) were characterized as potent MCHR1 antagonists. It has been found that the efficacy of compound 147a could be obtained with a safe cardiovascular profile.
A series of quinazoline-heterocyclic derivatives were prepared analogs to vasicinone (vasicine and vasicinone are major quinazoline alkaloids isolated from Justicia adhatoda L. and are known to have a moderate bronchodilatory effect), in which the vasicinone C-ring was replaced with the alkyl chain terminated by tertiary amine . The new derivatives (150) ([Figure 73]) displayed bronchodilatory effect at low micromolar concentrations (ED50 = 0.178–1.90 mmol/l, ED50 of theophylline 2.090 mmol/l, ED50 of vasicinone 2.864 mmol/l) on isolated rat trachea, and low toxicity both on Balb/c3T3 mouse fibroblast cells and in mice.
|Figure 73: Structures of quinazoline-heterocyclic derivatives analogous to vasicinone alkaloids.|
Click here to view
A new series of 6,7-bis(arylthio)-quinazoline-5,8-dione and furo [2,3-f]quinazolin-5-ol derivatives were prepared and evaluated as in-vitro antifungal agents against Candida spp., Aspergillus spp., and Cryptococcus neoformans. Among them, 2-amino-4-arylthio-5-hydroxyfuro [2,3-f]quinazoline derivatives (151a,b) ([Figure 74]) exhibited complete growth inhibition of the tested Candida spp. and Aspergillus spp. at an minimum inhibitory concentration (MIC) level of 12.5 μg/ml. The obtained data suggested that furo [2,3-f]quinazolines could be promising antifungal agents .
Maurya et al.  have synthesized various substituted 5,6-dihydro-8 methoxybenzo[h]quinazolin-2-amine derivatives in good yields, following an efficient method. Compounds 152a, 152b, and 152c ([Figure 75]) exhibited significant antitubercular activity at MIC values of 50, 100, and 50 μmol/l, respectively, in an in-vitro assay against the Mycobacterium tuberculosis H37Rv strain.
|Figure 75: Structures of 5,6-dihydro-8-methoxybenzo[h]quinazolin-2-amine derivatives.|
Click here to view
The 2-mercaptoquinazoline compound (153) exhibits antifungal activity through the physiological pathway and through cytotoxicity ([Figure 76]). It is hypothesized that it first attacks the cell wall and destroys the fungal cell, exerting its fungicidal effect through cytotoxicity. Second, it directly prevents energy metabolism, protein biosynthesis, and enzyme activity and indirectly prevents the building of the cell architecture through the physiological pathway .
A new set of 1-methyl-3-substituted quinazoline-2,4-dione derivatives were designed and prepared ([Figure 77]) . They were evaluated as chitin synthase inhibiting agents and as antifungal agents. Results showed that compounds 154a–d had a strong inhibitory effect against chitin synthase. Compound 154b showed the highest activity of IC50 = 0.08 mmol/l, whereas polyoxin B as a standard drug exhibited IC50 of 0.18 μmol/l.
|Figure 77: Structures of 1-methyl-3-substituted quinazoline-2,4-dione derivatives.|
Click here to view
Plasmodium, the parasite that infects humans with malaria, multiplies in the liver and is then released into circulating erythrocytes. Therefore, the erythrocyte cell membrane has an essential role in the potency of different antimalarial drugs or in inducing resistance against them. The antiplasmodial activity of N6-(4-methoxybenzyl)quinazoline-2, 4, 6-triamine (155) is produced in human erythrocytes and on their cell membranes  ([Figure 78]).
Chen et al.  identified several indole-based quinazoline derivatives with antihepatitis activity ([Figure 79]). SAR studies of the indole substituents optimized the potency and protein kinase (PK) properties. Optimization of C4, C5, and C6 substituents led to the formation of 4,5-furanylindole as the best core for antihepatitis activity. The C2 carboxylic acids exhibited better PK properties than the corresponding acylsulfonamides. Accordingly, the derivative (156) was considered as a promising lead with high activity. Leivers et al.  discovered small-molecule type III phosphatidylinositol 4-kinase α (PI4KIIIα) inhibitors as antihepatitis C virus (anti-HCV) agents. They have also described the methods for their preparation and SARs associated with their biological inhibition of PI4KIIIa and HCV replication. The biological data revealed that the pyridine-based quinazolinone derivative (157) has high selectivity for PI4KIIIa and potently inhibits HCV replication in vitro.
A new set of (1E,4E)-1-aryl-5-[2-(quinazolin-4-yloxy) phenyl]-1,4-pentadien-3-one derivatives has been prepared by Luo et al.. The derivatives were tested as antiviral agents. Antiviral bioassays proved that most of the compounds exhibited promising in-vivo antiviral bioactivity against the tobacco mosaic virus and the cucumber mosaic virus at 500 mg/ml. Also, it has been revealed that the compounds (158a–c) ([Figure 80]) could possess appreciable protective bioactivities on tobacco mosaic virus ex vivo by ∼50% (EC50) at 257.7, 320.7, and 243.3 mg/ml.
|Figure 80: Structures of (quinazolin-4-yloxy)phenyl-1,4-pentadien-3-one derivatives.|
Click here to view
Antitrypanosomatid and antiplasmodial activity
A novel set of 2, 4, 6-triaminequinazoline derivatives has been designed and synthesized as potential trypanocidal, leishmanicidal, and antiplasmodial agents . The new derivatives were rationalized using docking studies of the dihydrofolate reductase (from Trypanosoma cruzi, Leishmania major, and Plasmodium vivax) and pteridine reductase (from T. cruzi and L. major) architectures. All of the newly synthesized analogs were examined in vitro against both bloodstream trypomastigotes of T. cruzi (NINOA and INC-5 strains) and promastigotes of Leishmania mexicana (MHOM/BZ/61/M379 strain) and also for cytotoxicity using the Vero cell line. The derivatives (159b–d) ([Figure 81]) were the most active agents against T. cruzi, exhibiting better activity compared with standard drugs nifurtimox and benznidazole. Also, the analogs (159b–e) exhibited the strongest potency against L. mexicana, compared with glucantime (the reference drug). In the cytotoxicity assay, protozoa were more susceptible than Vero cells. In vivo, the Plasmodium berghei assay (ANKA strain) showed that the analogs (159a–e) had more potency than chloroquine and pyrimethamine (reference drugs) upon oral administration. The antiprotozoal potency of these compounds represents an important point in therapeutical chemistry in the treatment of Chagas’ disease, leishmaniosis, and malaria.
The derivative N6-(ferrocenmethyl)quinazolin-2, 4, 6-triamine (160) is one of a set of quinazoline-2, 4, 6-triamines ([Figure 82]) that were prepared and assessed in vitro against L. mexicana. It displayed potency on promastigotes and intracellular amastigotes stages of the parasite besides its drawbacks in human tissues. Interestingly, antiparasitic effect is mainly related to the presence of the ferrocene group. This moiety affords important characteristics to the molecule, primarily as a result of the readily oxidized iron atom. According to various studies, the ferrocene group can exert its effect through redox reactions by means of its ability to exert reactive oxygen species, principally the hydroxyl radicals. Additionally, the quinazoline-2,4-diamine scaffold is required for further biological activity.
Various quinazoline derivatives of miscellaneous activities
Amin et al.  synthesized a new class of spiro[(2H,3H)quinazoline-2,1′-cyclohexan]-4(1H)-one analogs as PARP-1 inhibitors. Twenty-one derivatives that exhibited the best fit to the target enzyme according to the docking study were selected to assess their in-vitro cytotoxic potency. It has been found that most of the synthesized quinazoline derivatives exhibited effective antiproliferative activity against breast carcinoma cell lines and showed effective inhibitory effect on the target PARP-1 enzyme (compounds 161–167) ([Figure 83]).
|Figure 83: Structures of spiro[(2H,3H)quinazoline-2,1′-cyclohexan]-4(1H)-one derivatives.|
Click here to view
Also, a series of spiroquinazoline-2,1′-cyclohexan-4(1H)-one derivatives conjugated to various aromatic and/or heterocyclic ring systems such as benzenesulfonamide, pyrazoline, oxazoline, pyrimidin-2-thione, 2-oxo(imino)pyridine, imidazoline, and thiazolidinone have been designed and synthesized as anti-inflammatory and analgesic agents . It has been found that the tested derivatives exhibited dual pharmacological activities with superior gastrointestinal safety profile compared with the reference drug indomethacin ([Figure 84]).
|Figure 84: Structures of novel derivatives of spiroquinazoline-2,1′-cyclohexan-4(1H)-one derivatives.|
Click here to view
Recently, a new set of hybrids bearing N-phenylquinazolin-4-amine and hydroxamic acid moieties (compounds 172) were synthesized and identified as dual VEGFR-2/HDAC (histone deacetylase-like protein) inhibitors with IC50 ranging in the nanomolar levels  ([Figure 85]).
|Figure 85: Structures of novel N-phenylquinazolin-4-amin-hydroxamic acid hybrids. HDAC, histone deacetylase; VEGFR-2, vascular endothelial growth factor receptor 2.|
Click here to view
A novel class of 7- or 8-substituted 4-morpholine-quinazoline compounds was designed and prepared. The inhibitory effects of the new derivatives against the PI3Kα enzyme and seven tumor cell lines, PC-3, DU145, MCF-7, BT474, SK-BR-3, U937, and A431, were examined in vitro. The derivative 173 exhibited high PI3Kα inhibition potency (IC50 = 4.2 nmol/l) and promising cancer activity. Also 173 displayed a remarkable inhibitory action against the PI3K/Akt/mTOR pathway as a potent PI3K inhibitor and anticancer agent , ([Figure 86]).
| Conclusion and perspectives|| |
Drug discovery and improvement of existing drugs has a pivotal role in the progress of therapeutic chemistry. Significant attention is being diverted to the development of the molecular architecture of heterocyclic compounds in (bio)organic chemistry. In this review, we have introduced a wide range of novel, effective, mild, and simple routes of synthesis to gain various substituted quinazoline and quinazolinone derivatives through readily available and cheap starting materials. Several strategies including metal-catalyzed reactions, MW irradiation, and conventional heating methods have been successfully employed to achieve these diversely decorated skeletons, which are of significant importance in pharmaceutical and agrochemical industries. This review also discusses numerous biological targets with significant bioactivities. Several quinazoline-based and quinazolinone-based drugs have already made their way to clinics and are being successfully used against various disorders. The SAR showed that obtaining the required biological potency for the synthesized compounds depends on the selection of a suitable substitution pattern, including electron-donating and electron-withdrawing, as well as some heterocyclic moieties, on the basic backbone. Furthermore, because of the simplicity of synthetic methods enabling the construction of core scaffolds of many marketed drugs, we hope to see further research in the design of novel functionalized quinazoline and quinazolinone derivatives, with exploitation of their biological activities in diverse ways. Chemical and biological studies should be continued on these scaffolds with the aim to obtain novel drugs with various biological activities of high selectivity and potency and devoid of the side effects of the parent drugs.
The authors are grateful to National Research Centre, Cairo, Egypt.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Reddy PS, Reddy PP, Vasantha T. A review on 2-heteryl and heteroalkyl-4(3H) quinazolinones. Heterocycles 2003; 60:183–226.
El-Hiti GA. Synthesis of substituted quinazolin-4(3H)-ones and quinazolines via directed lithiation. Heterocycles 2000; 53:1839–1868.
Verhaeghe P, Azas N, Gasquet M, Hutter S, Ducros C, Laget M et al.
Synthesis and antiplasmodial activity of new 4-aryl-2-trichloromethyl quinazolines. Bioorg Med Chem Lett 2008; 18:396–401.
Grover G, Kini SG. Synthesis and evaluation of new quinazolone derivatives of nalidixic acid as potential antibacterial and antifungal agents. Eur J Med Chem 2006; 41:256–262.
Smits RA, Adami M, Istyastono EP, Zuiderveld OP, van Dam CME, de Kanter FJJ et al.
Synthesis and QSAR of quinazolinesulfonamides as highly potent human histamine H4 receptor inverse agonists. J Med Chem 2010; 53:2390–2400.
Georgey H, Abdel-Gawad N, Abbas S. Synthesis and anticonvulsant activity of some quinazolin-4-(3H)-one derivatives. Molecules 2008; 13:2557–2569.
Jain KS, Bariwal JB, Kathiravan MK, Phoujdar MS, Sahne RS, Chauhan AK, Shah Yadav MR. Recent advances in selective alpha1-adrenoreceptor B.S. antagonists as antihypertensive agents. Bioorg Med Chem 2008; 16:4759–4800.
Malamas MS, Millen J. Quinazoline acetic acids and related analogues as aldose reductase inhibitors. J Med Chem 1991; 34:1492–1503.
Shallal HM, Russu WA. Discovery, synthesis, and investigation of the antitumor activity of novel piperazinylpyrimidine derivatives. Eur J Med Chem 2011; 46:2043–2057.
Chilin A, Conconi MT, Marzaro G, Guiotto A, Urbani L, Tonus F, Parnigotto P. Exploring epidermal growth factor receptor (EGFR) inhibitor features: the role of fused dioxygenated rings on the quinazoline scaffold. J Med Chem 2010; 53:1862–1866.
Sagiv-Barfi I, Weiss E, Levitzki A. Design, synthesis, and evaluation of quinazoline T cell proliferation inhibitors. Bioorg Med Chem 2010; 18:6404–6413.
Fry DW, Kraker AJ, McMichael A, Ambroso LA, Nelson JM, Leopold WR et al.
A specific inhibitor of the epidermal growth factor receptor tyrosine kinase. Science 1994; 265:1093–1095.
Lewerenz A, Hentschel S, Vissiennon Z, Michael S, Nieber K. A3 receptors in cortical neurons: pharmacological aspects and neuroprotection during hypoxia. Drug Dev Res 2003; 58:420–427.
Malecki N, Carato P, Rigo G, Goossens JF, Houssin R, Bailly C, Henichart JP. Synthesis of condensed quinolines and quinazolines as DNA ligands. Bioorg Med Chem 2004; 12:641–647.
Wattanapiromsakul C, Forster PI, Waterman PG. Alkaloids and limonoids from Bouchardatia neurococca: systematic significance. Phytochemistry 2003; 64:609–615.
Gabriel S. Synthesis and pharmacological Evaluation of 3-alkyl/aryl–2- methylquinazolin-4-one derivatives. Ber 1903; 36:800–845.
Asif M. Chemical characteristics, synthetic methods, and biological potential of quinazoline and quinazolinone derivatives. Int J Med Chem 2014; 2014:1–27.
Paal and BuschChemistry and structral activity relationship of quinazoline compounds. Ber 188; 22:2683–2694.
Alexandre F, Berecibar A, Wrigglesworth R, Besson T. Novel series of 8H-quinazolino[4,3-b]quinazolin-8-ones via two Niementowski condensations. Tetrahedron 2003; 59:1413–1419.
Witt A, Bergman J. Synthesis and reactions of some 2-Vinyl-3H
-quinazolin-4-ones. Tetrahedron 2000; 56:7245–7253.
McKee MK, McKee RL, Bost RW. 7-Chloro-4-(1-diethylamino-4-pentylamino)-quinazoline. J Am Chem Soc 1947; 69:184–1184.
Qiao RZ, Xu BL, Wang YH. A facile synthesis of 2-substituted-2,3-dihydro-4(1H)-quinazolinones in 2,2,2-trifluoroethanol. Chin Chem Lett 2007; 18:656–658.
Rad-Moghadam K, Mohseni M. An expeditious and solvent-free route to the synthesis of 2-substituted quinazolin-4(3H)-ones under microwave conditions. J Chem Res 2003; 8:487–488.
Nouira I, Kostakis IK, Dubouilh C, Chosson E, Iannelli M, Besson T. Decomposition of formamide assisted by microwaves, a tool for synthesis of nitrogen-containing heterocycles. Tetrahedron Lett 2008; 49:7033–7036.
Abdel-Jalil RJ, Voelter W, Saeed M. A novel method for the synthesis of 4(3H)-quinazolinones. Tetrahedron Lett 2004; 45:3475–3476.
Erba E, Pocor D, Valle M. ν-Triazolines. Part 41. A new synthesis of 2-alkylquinazolines and 2,9-dialkylpyrimido[4,5-b]indoles. J Chem Soc Perkin Trans 1999; 1:421–426.
Kotsuki H, Sakai H, Morimoto H, Suenaga H. A new quinazoline synthesis. Synlett 1999; 12:1993–1995.
Hess HJ, Cronin TH, Scriabine A. Antihypertensive 2-amino-4(3H)-quinazolinones. J Med Chem 1968; 11:130–136.
Clark RH, Wagner EC. Isatoic anhydride. I. Reaction with primary and secondary amines and with some amides. J Org Chem 1944; 9:55–67.
Majo VJ, Perumal PT. Dimerization of substituted 2-aminobenzoic acids under Vilsmeier conditions: a novel route to the synthesis of 4-(3H)-quinazolinones. Tetrahedron Lett 1996; 37:5015–5018.
Rewcastle GW, Palmer BD, Bridges AJ, Showalter HD, Sun L, Nelson J et al.
Tyrosine kinase inhibitors. 9. Synthesis and evaluation of fused tricyclic quinazoline analogues as ATP site inhibitors of the tyrosine kinase activity of the epidermal growth factor receptor. J Med Chem 1996; 39:918–928.
Szczepankiewicz W, Suwinski J, Bujok R. Synthesis of 4-arylaminoquinazolines and 2-aryl-4-arylaminoquinazolines from 2-aminobenzonitrile, anilines and formic acid or benzaldehydes. Tetrahedron 2000; 56:9343–9349.
Tsou HR, Mamuya N, Johnson BD, Reich MF, Gruber BC, Ye F et al.
6-Substituted-4-(3-bromophenylamino)quinazolines as putative irreversible inhibitors of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER-2) tyrosine kinases with enhanced antitumor activity. J Med Chem 2001; 44:2719–2734.
Yoon DS, Han Y, Stark TM, Haber JC, Gregg BT, Stankovich SB. Efficient synthesis of 4-aminoquinazoline and thieno[3,2-d]pyrimidin-4-ylamine derivatives by microwave irradiation. Org Lett 2004; 6:4775–4778.
Ager IR, Harrison DR, Kennewell PD, Taylor JB. Synthesis and central nervous system activity of quinazolones related to 2-methyl-3-(o-tolyl)-4(3H)-quinazolone (methaqualone). J Med Chem 1977; 20:379–386.
Jeong JU, Chem X, Rahman A, Yamashita DS, Lengo JL. An efficient synthesis of 3-substituted 3H-pyrimidin-4-ones. Org Lett 2004; 6:1013–1016.
Welch WM, Ewing FE, Huang J, Menniti FS, Pagnozzi MJ, Kelly K et al.
Atropisomeric quinazolin-4-one derivatives are potent noncompetitive (-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists. Bioorg Med Chem Lett 2001; 11:177–181.
Dandia A, Singh R, Savawgi P. Green chemical multi-component one-pot synthesis of fluorinated 2,3-disubstituted quinazolin-4(3H)-ones under solvent-free conditions and their anti-fungal activity. J Fluorine Chem 2005; 126:307–312.
Lee HS, Chang YG, Kim K. A facile synthesis of 3-substituted 2-cyanoquinazolin-4(3H)-ones and 3-alkyl-2-cyanothieno[3,2-d]pyrimidin-4(3H)-ones via 1,2,3-dithiazoles. J Heterocycl Chem 1998; 35:659–668.
Seijas JA, Vazquez-Tato MP, Martınez MM. Microwave enhanced synthesis of 4-aminoquinazolines. Tetrahedron Lett 2000; 41:2215–2217.
Mizuno T, Okamoto N, Ito T, Miyata T. Synthesis of 2,4-dihydroxyquinazolines using carbon dioxide in the presence of DBU under mild conditions. Tetrahedron Lett 2000; 41:1051–1053.
Kaname M, Tsuchiya T, Sashida H. Thermal ring contraction of 3H-1,4-benzodiazpines into quinazolines. Heterocycles 1999; 51:2407–2413.
Zielinski W, Kudelko A, Holt EM. Synthesis of 2,4-diaminoquinazoline derivatives. Heterocycles 1998; 48:319–328.
Bergman J, Brynolf A, Elman B, Vuorinen E. Synthesis of quinazolines. Tetrahedron 1986; 42:3697–3706.
Keen N, Taylor S. Aurora-kinase inhibitors as anticancer agents. Nat Rev Cancer 2004; 4:927–936.
Foote KM, Mortlock AA, Heron NM, Jung FH, Hill GB. Synthesis and SAR of 1-acetanilide-4-aminopyrazolesubstituted quinazolines: selective inhibitors of aurora B kinase with potent anti-tumor activity. Bioorg Med Chem Lett 2008; 18:1904–1909.
Sharma A, Luxami V, Paul K. Synthesis, single crystal and antitumor activities of benzimidazole-quinazoline hybrids. Bioorg Med Chem Lett 2013; 23:3288–3294.
Paul K, Sharma A, Luxami V. Synthesis and in vitro antitumor evaluation of primary amine substituted quinazoline linked benzimidazole. Bioorg Med Chem Lett 2014; 24:624–629.
Cai J, Sun M, Wu X, Chen J, Wang P, Zong X, Ji M. Design and synthesis of novel 4-benzothiazole amino quinazolines dasatinib derivatives as potential anti-tumor agents. Eur J Med Chem 2013; 63:702–712.
Barbosa MLC, Lima LM, Tesch R, Mauricio CRS, Totzke F, Kubbutat MHG. Novel 2-chloro-4-anilino-quinazoline derivatives as EGFR and VEGFR-2 dual inhibitors. Eur J Med Chem 2014; 71:1–14.
Abouzid K, Shouman S. Design, synthesis and in vitro antitumor activity of 4-aminoquinoline and 4-aminoquinazoline derivatives targeting EGFR tyrosine kinase. Bioorg Med Chem 2008; 16:7543–7551.
Zhang HJ, Wang SB, Quan ZS. Synthesis and antidepressant activities of 4-(substituted-phenyl)tetrazolo[1,5-a]quinazolin-5(4H)-ones and their derivatives. Mol Divers 2015; 19:817–828.
Lim CJ, Oh KS, Ha JD, Lee JH, Seo HW, Chae CH et al.
4-Substituted quinazoline derivatives as novel EphA2 receptor tyrosine kinase inhibitors. Bioorg Med Chem Lett 2014; 24:4080–4083.
Yao H, Ji M, Zhu Z, Zhou J, Cao R, Chen X, Xu B. Discovery of 1-substituted benzyl-quinazoline-2,4(1H,3H)-dione derivatives as novel poly(ADP-ribose)polymerase-1 inhibitors. Bioorg Med Chem 2015; 23:681–693.
Li S, Wang X, He Y, Zhao M, Chen Y, Xu J et al.
Design and synthesis of novel quinazoline nitrogen mustard derivatives as potential therapeutic agents for cancer. Eur J Med Chem 2013; 67:293–301.
Spanò V, Montalbano A, Carbone A, Parrino B, Diana P, Cirrincione G et al.
Synthesis of a new class of pyrrolo[3,4-h]quinazolines with antimitotic activity. Eur J Med Chem 2014; 74:340–357.
Alanazi AM, Abdel-Aziz AAM, Al-Suwaidan IA, Abdel-Hamide SG, Shawer TZ, El-Azab AS. Design, synthesis and biological evaluation of some novel substituted quinazolines as antitumor agents. Eur J Med Chem 2014; 79:446–454.
Elkamhawy A, Viswanath ANI, Pae AN, Kim HY, Heo JC, Park WK et al.
Discovery of potent and selective cytotoxic activity of new quinazoline-ureas against TMZ-resistant glioblastoma multiforme (GBM). Eur J Med Chem 2015; 103:210–222.
Xu L, Russu WA. Molecular docking and synthesis of novel quinazoline analogues as inhibitors of transcription factors NF-(B activation and their anti-cancer activities. Bioorg Med Chem 2013; 21:540–546.
Wang XM, Xin MH, Xu J, Kang BR, Li Y, Lu SM, Zhang SQ. Synthesis and antitumor activities evaluation of m-(4-morpholinoquinazolin-2-yl)benzamides in vitro and in vivo. Eur J Med Chem 2015; 96:382–395.
Fares M, Eldehna WM, Abou-Seri SM, Abdel-Aziz HA, Aly MH, Tolba MF. Design, synthesis and in vitro antiproliferative activity of novel isatin-quinazoline hybrids. Arch Pharm (Weinheim) 2015; 348:144–154.
Cohen MH, Williams GA, Sridhara R, Chen G, Pazdur R. FDA drug approval summary: gefitinib (ZD1839) (Iressa (R)) tablets. Oncologist 2003; 8:303–306.
Cohen MH, Johnson JR, Chen YF, Sridhara R, Pazdur R. FDA drug approval summary: erlotinib (Tarceva (R)) tablets. Oncologist 2005; 10:461–466.
Kris MG, Natale RB, Herbst RS, Lynch TJJr, Prager D, Belani CP et al.
Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 2003; 290:2149–2158.
Brullo C, Rocca M, Fossa P, Cichero E, Barocelli E, Ballabeni V et al.
Synthesis of new 5,6-dihydrobenzo[h]quinazoline 2,4-diamino substituted and antiplatelet/antiphlogistic activities evaluation. Bioorg Med Chem Lett 2012; 22:1125–1129.
Pu Y, Cao D, Xie C, Pei H, Li D, Tang M, Lijuan C. Anti-arthritis effect of a novel quinazoline derivative through inhibiting production of TNF-α mediated by TNF-α converting enzyme in murine collagen-induced arthritis model. Biochem Biophys Res Commun 2015; 462:288–293.
Hu J, Zhang Y, Dong L, Wang Z, Chen L, Liang D et al.
Design, synthesis, and biological evaluation of novel quinazoline derivatives as anti-inflammatory agents against lipopolysaccharide-induced acute lung injury in rats. Chem Biol Drug Des 2015; 85:672–684.
Hussein MA. Synthesis, anti-inflammatory, and structure antioxidant activity relationship of novel 4-quinazoline. Med Chem Res 2013; 22:4641–4653.
Eweas AF, El-Nezhawy AOH, Baiuomy AR, Awad MM. Design, synthesis, anti-inflammatory, analgesic screening, and molecular docking of some novel 2-pyridyl (3H)-quinazolin-4-one derivatives. Med Chem Res 2013; 22:1011–1020.
Saravanan G, Alagarsamy V, Prakash CR. Synthesis, analgesic, anti-inflammatory, and in vitro antimicrobial activities of some novel quinazolin-4(3H)-one derivatives. Med Chem Res 2013; 22:340–350.
Farag AA, Khalifa EM, Sadik NA, Abbas SY, Al-Sehemi AG, Ammar YA. Synthesis, characterization, and evaluation of some novel 4(3H)-quinazolinone derivatives as anti-inflammatory and analgesic agents. Med Chem Res 2013; 22:440–452.
Al-Salahi RA, Gamal-Eldeen AM, Alanazi AM, Al-Omar MA, Marzouk MA, Fouda MMG. Cytotoxicity and anti-inflammatory activity of methylsulfanyl-triazoloquinazolines. Molecules 2013; 18:1434–1446.
Zayed MF, Hassan MH. Synthesis and biological evaluation studies of novel quinazolinone derivatives as antibacterial and anti-inflammatory agents. Saudi Pharm J 2013; 22:157–162.
Bhaduri A, Khanna N, Dhar M. Potential anticonvulsants synthesis of 2,3-disubstituted-4-quinazolinones and quinazolino-4-thiones. Indian J Chem 1964; 2:159–166.
Badr MZA, El-Sherief HAH, Mahmoud AM. Studies on synthesis of 6-bromo-2,3-disubstituted 4-quinazolinones and their thi ones. Bull Chem Soc Jpn 1980; 53:2389–2392.
El-Azab AS, El-Tahir KEH. Synthesis and anticonvulsant evaluation of some new 2,3,8-trisubstituted-4(3H)-quinazoline derivatives. Bioorg Med Chem Lett 2012; 22:1879–1885.
Ugale VG, Bari SB. Quinazolines: new horizons in anticonvulsant therapy. Eur J Med Chem 2014; 80:447–501.
Colotta V, Lenzi O, Catarzi D, Varano F, Squarcialupi L, Costagli C et al.
3-hydroxy-1H-quinazoline-2,4-dione derivatives as new antagonists at ionotropic glutamate receptors: molecular modeling and pharmacological studies. Eur J Med Chem 2012; 54:470–482.
Varano F, Catarzi D, Colotta V, Lenzi O, Filacchioni G, Galli A, Costagli C. Novel AMPA and kainate receptor antagonists containing the pyrazolo[1,5]quinazoline ring system: synthesis and structure-activity relationships. Bioorg Med Chem 2008; 16:2617–2626.
Jatav V, Mishra P, Kashaw S, Stables J. Synthesis and CNS depressant activity of some novel 3-[5-substituted1,3,4-thiadiazole-2-yl]-2-styryl quinazoline-4(3H)-ones. Eur J Med Chem 2008; 43:135–141.
Misra R, Chaturvedi A, Rao N, Parmar S. Anticonvulsant and monoamine oxidase inhibitory properties of newer chlorostrylquinazolones. Pharmacol Res Commun 1979; 11:623–633.
Catarzi D, Lenzi O, Colotta V, Varano F, Poli D, Filacchioni G et al.
Pharmacological characterization of some selected 4,5-dihydro-4-oxo-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylates and 3-hydroxyquinazoline-2,4-diones as (S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)-propionic acid receptor antagonists. Chem Pharm Bull 2010; 58:908–911.
Zheng Y, Bian M, Deng XQ, Wang SB, Quan ZS. Synthesis and anticonvulsant activity evaluation of 5-phenyl-[1,2,4]triazolo[4,3-c]quinazolin-3-amines. Arch Pharm (Weinheim) 2012; 346:119–126.
Kadi AA, El-Azab AS, Alafeef AM, Abdel-Hamide S. Synthesis and biological screening of some new substituted 2-mercapto-4-(3H)-quinazolinone analogs as anticonvulsant agents. Az J Pharm Sci 2009; 34:135–155.
Orain D, Ofner S, Koller M, Carcache DA, Froestl W, Allgeier H et al.
6-Amino quinazolinedione sulfonamides as orally active competitive AMPA receptor antagonists. Bioorg Med Chem Lett 2012; 22:996–999.
Koller M, Lingenhoehl K, Schmutz M, Vranesic I-T, Kallen J, Auberson YP et al.
Quinazolinedione sulfonamides: a novel class of competitive AMPA receptor antagonists with oral activity. Bioorg Med Chem Lett 2011; 21:3358–3361.
Floersheim P, Allgeier, H, Froestl W, Koller M, Mattes H, Nozulak J, et al. Quinazoline derivatives. EP Pat. 1773788; 14 November 2012.
Elkamhawy A, Lee J, Park BG, Park I, Pae AN, Roh EJ. Novel quinazoline-urea analogues as modulators for Ab-induced mitochondrial dysfunction: design, synthesis, and molecular docking study. Eur J Med Chem 2014; 84:466–475.
Kumar D, Kaur G, Negi A, Kumar S, Singh S, Kumar R. Synthesis and xanthine oxidaseinhibitory activity of 5,6-dihydropyrazolo/pyrazolo[1,5-c]quinazoline derivatives. Bioorg Chem 2014; 57:57–64.
Nour A, Hayashi T, Chan M, Yao S, Tawatao IR, Crain B. Discovery of substituted 4-aminoquinazolines as selective Toll-like receptor 4 ligands. Bioorg Med Chem Lett 2014; 24:4931–4938.
Deng X, Guo L, Xu L, Zhen X, Yu K, Zhao W, Fu W. Discovery of novel potent and selective ligands for 5-HT2A receptor with quinazoline scaffold. Bioorg Med Chem Lett 2015; 25:3970–3974.
Zhang L, Yang Y, Zhou H, Zheng Q, Li Y, Zheng S et al.
Structure-activity study of quinazoline derivatives leading to the discovery of potent EGFR-T790 M inhibitors. Eur J Med Chem 2015; 102:445–463.
Pham TAN, Yang Z, Fang Y, Luo J, Lee J, Park H. Synthesis and biological evaluation of novel 2,4-disubstituted quinazoline analogues as GPR119 agonists. Bioorg Med Chem 2013; 21:1349–1356.
Sasmal S, Balasubrahmanyam D, Kanna Reddy HR, Balaji G, Srinivas G, Cheera S et al.
Design and optimization of quinazoline derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists: part 2. Bioorg Med Chem Lett 2012; 22:3163–3167.
Spulák M, Pourová J, Voprsálová M, Mikuse J, Kunes J, Vacek J et al.
Novel bronchodilatory quinazolines and quinoxalines: synthesis and biological evaluation. Eur J Med Chem 2014; 74:65–72.
Ryu CK, Kim YH, Im HA, Kim JY, Yoon JH, Kim A. Synthesis and antifungal activity of 6,7-bis(arylthio)-quinazoline-5,8-diones and furo[2,3-f]quinazolin-5-ols. Bioorg Med Chem Lett 2012; 22:500–503.
Maurya HK, Verma R, Alam S, Pandey S, Pathak V, Sharma S et al.
Studies on substituted benzo[h]quinazolines, benzo[g]indazoles, pyrazoles, 2,6-diarylpyridines as anti-tubercular agents. Bioorg Med Chem Lett 2013; 23:5844–5849.
Rojas-Aguirre Y, Hernández-Luis F, Mendoza-Martínez C, Sotomayor CP, Aguilar LF, Villena F et al.
Effects of an antimalarial quinazoline derivative on human erythrocytes and on cell membrane molecular models. Biochim Biophys Acta 2012; 1818:738–746.
Liu F, Huang Y. Antifungal bioactivity of 6-bromo-4-ethoxyethylthio quinazoline. Pest Biochem Physiol 2011; 101:248–255.
Ji Q, Yang D, Wang X, Chen C, Deng Q, Ge Z et al.
Design, synthesis and evaluation of novel quinazoline-2,4-dione derivatives as chitin synthase inhibitors and antifungal agents. Bioorg Med Chem 2014; 22:3405–3413.
Chen KX, Venkatraman S, Anilkumar GN, Zeng Q, Lesburg CA, Vibulbhan B, Velazquez F. Discovery of SCH 900188: a potent hepatitis C virus NS5B polymerase inhibitor prodrug as a development candidate. ACS Med Chem Lett 2014; 5:244–248.
Leivers AL, Tallant M, Shotwell JB, Dickerson S, Leivers MR, McDonald OB et al.
Discovery of selective small molecule type III phosphatidylinositol 4-kinase alpha (PI4KIIIa) inhibitors as anti hepatitis C (HCV) agents. J Med Chem 2014; 57:2091–2106.
Luo H, Liu J, Jin L, Hu D, Chen Z, Yang S et al.
Synthesis and antiviral bioactivity of novel (1E,4E)-1-aryl-5(2-(quinazolin-4-yloxy)phenyl)-1,4-pentadien-3-one derivatives. Eur J Med Chem 2013; 63:662–669.
Mendoza-Martínez C, Galindo-Sevilla N, Correa-Basurto J, Ugalde-Saldivar VM, Rodríguez-Delgado RG, Hernandez-Pineda J et al.
Antileishmanial activity of quinazoline derivatives: synthesis, docking screens, molecular dynamic simulations and electrochemical studies. Eur J Med Chem 2015; 92:314–331.
Amin KM, Anwar MM, Syam YM, Khedr M, Kamel MM, Kassem EMM. A novel class of substituted spiro[quinazoline-2,1′-cyclohexane] derivatives as effective PARP-1 inhibitors: molecular modeling, synthesis, cytotoxic and enzyme assay evaluation. Acta Pol Pharm 2013; 70:687–708.
Amin KM, Anwar MM, Kamel MM, Kassem EMM, Syam YM, Elseginy SA. Synthesis, cytotoxic evaluation and molecular docking study of novel quinazoline derivatives as PARP-1 inhibitors. Acta Pol Pharm 2013; 70:833–849.
Peng WP, Xuan J, Wu TT, Xue JY, Ren ZW, Liu DK et al.
Design, synthesis and biological evaluation of N-phenylquinazolin-4-amine hybrids as dual inhibitors of VEGFR-2 and HDAC. Eur J Med Chem 2016; 109:1–12.
Peng W, Tu ZC, Long ZJ, Liu Q, Lu G. Discovery of 2-(2-aminopyrimidin-5-yl)-4-morpholino-N-(pyridin-3-yl)quinazolin-7-amines as novel PI3K/mTOR inhibitors and anticancer agents. Eur J Med Chem 2016; 108:644–654.
Wilson D, Fanning L Krenitsky P, Boger J. Quinazolines useful as modulators of ion channels. U.S. Pat. 7718658; 18 May 2010.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14], [Figure 15], [Figure 16], [Figure 17], [Figure 18], [Figure 19], [Figure 20], [Figure 21], [Figure 22], [Figure 23], [Figure 24], [Figure 25], [Figure 26], [Figure 27], [Figure 28], [Figure 29], [Figure 30], [Figure 31], [Figure 32], [Figure 33], [Figure 34], [Figure 35], [Figure 36], [Figure 37], [Figure 38], [Figure 39], [Figure 40], [Figure 41], [Figure 42], [Figure 43], [Figure 44], [Figure 45], [Figure 46], [Figure 47], [Figure 48], [Figure 49], [Figure 50], [Figure 51], [Figure 52], [Figure 53], [Figure 54], [Figure 55], [Figure 56], [Figure 57], [Figure 58], [Figure 59], [Figure 60], [Figure 61], [Figure 62], [Figure 63], [Figure 64], [Figure 65], [Figure 66], [Figure 67], [Figure 68], [Figure 69], [Figure 70], [Figure 71], [Figure 72], [Figure 73], [Figure 74], [Figure 75], [Figure 76], [Figure 77], [Figure 78], [Figure 79], [Figure 80], [Figure 81], [Figure 82], [Figure 83], [Figure 84], [Figure 85], [Figure 86]
|This article has been cited by|
||Palladium-catalyzed synthesis of novel trifluoromethylated quinazolinone, N-arylquinazoline and N-benzylquinazoline derivatives
| ||Mahdieh Sadat Sajadi,Elham Kazemi,Ali Darehkordi |
| ||Tetrahedron Letters. 2021; 71: 153053 |
|[Pubmed] | [DOI]|
||Synthesis and Some Reactions of 3-Aminospiro[benzo[h]quinazoline-5,1'-cycloheptanes]
| ||A. I. Markosyan,A. S. Ayvazyan,S. A. Gabrielyan,S. S. Mamyan |
| ||Russian Journal of Organic Chemistry. 2021; 57(3): 383 |
|[Pubmed] | [DOI]|
||Chemical Insights Into the Synthetic Chemistry of Quinazolines: Recent Advances
| ||Muhammad Faisal,Aamer Saeed |
| ||Frontiers in Chemistry. 2021; 8 |
|[Pubmed] | [DOI]|
||Current Progress in Quinazoline Derivatives as Acetylcholinesterase and Monoamine Oxidase Inhibitors
| ||Nisha Abdul Rehuman,Abdullah G. Al-Sehemi,Della Grace Thomas Parambi,T. M. Rangarajan,Orazio Nicolotti,Hoon Kim,Bijo Mathew |
| ||ChemistrySelect. 2021; 6(28): 7162 |
|[Pubmed] | [DOI]|
||Dihydroquinazolin-4(1H)-one derivatives as novel and potential leads for diabetic management
| ||Oluwatoyin Babatunde,Shehryar Hameed,Uzma Salar,Sridevi Chigurupati,Abdul Wadood,Ashfaq Ur Rehman,Vijayan Venugopal,Khalid Mohammed Khan,Muhammad Taha,Shahnaz Perveen |
| ||Molecular Diversity. 2021; |
|[Pubmed] | [DOI]|
||Design, Synthesis and Evaluation of 2,4-Diaminoquinazoline Derivatives as Potential Tubulin Polymerization Inhibitors
| ||Frida S. Herrera-Vázquez,Félix Matadamas-Martínez,Rodrigo Aguayo-Ortiz,Laura Dominguez,Teresa Ramírez-Apan,Lilián Yépez-Mulia,Francisco Hernández-Luis |
| ||ChemMedChem. 2020; |
|[Pubmed] | [DOI]|
||Synthesis, characterization, and investigation of the anti-inflammatory effect of 2,3-disubstituted quinazoline-4(1H)-one
| ||Bhimrao Ghodge,Ajay Kshirsagar,Vijay Navghare |
| ||Beni-Suef University Journal of Basic and Applied Sciences. 2020; 9(1) |
|[Pubmed] | [DOI]|